Registration Dossier

Administrative data

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
experimental study planned
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out : 2-(2-(2-methoxyethoxy)ethoxy)ethanol (EC 203-962-1, CAS 112-35-6)

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION [please address all points below]:
- Available GLP studies : None for this end point
- Available non-GLP studies : None for this end point
- Historical human data : None
- (Q)SAR : No suitable QSAR available.
- In vitro methods : no suitable in vitro methods available
- Weight of evidence : No studies available for this substance for this end point.
- Grouping and read-across : Data is available for other E series glycol ethers but not within the methyl series. The data is not considered sufficient to meet current required quality standards.

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- The substance is not a genotoxic carcinogen nor a germ cell mutagen. It is not classified for developmental toxicity. It is not toxicologically inactive. The end point cannot therefore be waived.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed. The basic study design is proposed. Dosing will be limited to a maximum of 1000mg/kgbw/day (or lower if indicated by range finder study) as there is no justification based on likely human exposure to exceed this.

Data source

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
GLP compliance:
yes
Limit test:
no
Justification for study design:
SPECIFICATION OF STUDY DESIGN FOR EXTENDED ONE-GENERATION REPRODUCTION TOXICITY STUDY WITH JUSTIFICATIONS

- Premating exposure duration for parental (P0) animals : 10 weeks. The standard ten week premating exposure is proposed for this study.
- Basis for dose level selection : A range finder study (OECD421) will be carried out before the main study. Route of exposure will be oral. A maximum dose of 1000mg/kgbw/day will be used.
- Inclusion/exclusion of extension of Cohort 1B : Excluded The existing data does not indicate the need to include a 2nd generation. The main use for the substance is as an intermediate and in hydraulic fluids. The use of hydraulic fluids is a wide dispersive use but in closed systems. Consumers will rarely come into significant contact with automotive brake fluid. DIY consumers will use such products a limited number of times per year if at all. Professional garage users may come into contact but such users will used closed systems to replace the hydraulic fluid in vehicles. The opportunity will be low and most likely be by dermal exposure only. Comparing the existing data for repeat dose toxicity shows that dermal uptake is low (the dermal NOAEL is 10x that for the oral route). According to the potential intrinsic hazard triggers: the substance is not genotoxic (full in vitro genotoxicity dataset available and negative; toxicokinetic information shows that the substance and most of its metaboites have a half life of 3-4hrs. One metabolite, and likely the one with toxic properties, has a half life of 17hrs in rats. (Daily dosing would suggest that the concentration would exceed 99% of the theoretical maximum steady state based on this half life within 4 days. This is not regarded as an extended exposure time and indicates maximal exposures would be seen within a single generation.) There are no indications of any effects related to endocrine disruption. The criteria for a second generation are therefore not met.
- Termination time for F2 : as per guideline.
- Inclusion/exclusion of developmental neurotoxicity Cohorts 2A and 2B : Excluded. There is no evidence that cohorts 2A and 2B are required (developmental neurotoxicity). There is a In a guideline (OECD 408) and GLP developmental neurotoxicity study available where rats were exposure to the substance in drinking water up to doses 4000mg/kgbw/day for 90 days. Such exposures did not result in clinical signs of toxicity, alterations in the functional observational battery (FOB), or gross or microscopic lesions in the nervous system. Minor decreases in motor activity were observed in the 4 g/kg/day treatment group at the Day 60 (males only) and Day 90 (males and females) evaluation periods. These decreases in motor activity were not considered to be neurotoxicologically significant based on the small magnitude of the changes, the parallel changes observed in body weights at these evaluation periods, and the lack of corroborative behavioral effects from the FOB evaluations or histological changes in central or peripheral nervous system tissues. Based on these findings 4 g/kg/day is a subchronic NOAEL for TGME neurotoxicity. No further investigation of this end point is warranted.
- Inclusion/exclusion of developmental immunotoxicity Cohort 3 :
There is no evidence that cohort 3 is required (Developmental immunotoxicity). Excluded. There is a guideline (OECD 408) and GLP oral repeat dose studywhere rats were exposure to TEGME in the drinking water for 90 days. The LOAEL was established to be 1200mg/kgbw/day, based on and changes to the liver. The NOAEL was 400mg/kgbw/day. No adverse changes were seen in the haematology or changes to organs associated with the immune system
- Route of administration : oral, either drinking water or gavage:

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
no data, secondary source of information.

Test animals

Species:
rat
Sex:
male/female

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
water
Doses / concentrations
Remarks:
It is expected that the maximum tested dose will be 1000mg/kgbw/day based on existing study information.
Control animals:
yes, concurrent vehicle

Results and discussion

Applicant's summary and conclusion